Thiopyrimidinecarboxamides as CXCR1/2 modulators

ABSTRACT

There is disclosed a pyrimidinecarboxamide compound useful as a pharmaceutical agent, synthetic processes, and pharmaceutical compositions which include the pyrimidinecarboxamide compound. More specifically, there is disclosed a CXCR1/2 inhibitor useful for treating a variety of inflammatory and neoplastic disorders.

TECHNICAL FIELD

The present disclosure provides pyrimidinecarboxamides useful aspharmaceutical agents, synthesis processes, and pharmaceuticalcompositions which include pyrimidinecarboxamide compounds. Morespecifically, the present disclosure provides CXCR1/2 inhibitorcompounds that are useful for treating a variety of inflammatory andneoplastic disorders.

BACKGROUND

Chemokines are chemotactic proteins that have the potential to attractmacrophages, T-cells, eosinophils, basophils, neutrophils andendothelial cells to sites of inflammation and tumor growth. Chemokinesare typically low molecular mass (7-9 kD) proteins that can be dividedinto four subfamilies: CC (or β-chemokines), CXC, C (or γ-chemokines)and CX3C (or δ-chemokines). The chemokines are categorized through theirprimary amino acid structure. The CXC subfamily is characterized by twoconserved Cys residues (C) near the N-terminus and separated by an aminoacid (X). The CXC-chemokines include, for example, interleukin-8 (IL-8),neutrophil-activating protein-1 (NAP-1), neutrophil-activating protein-2(NAP-2), GROα, GROβ, GROγ, ENA-78, GCP-2, IP-10, MIG and PF4. The CXCsubfamily of chemokines is further characterized by the presence orabsence of a specific amino acid sequence, glutamicacid-leucine-arginine (or ELR for short) immediately before the firstCys residue of the CXC motif. Those chemokines with the ELR motif(ELRCXC) are important for the recruitment and activation of neutrophilsto sites of inflammation. GROα and IL-8 are examples of ELRCXCchemokines.

The CXC-chemokines mediate their chemotactic activity throughinteraction with the chemokine receptors CXCR1 and CXCR2. CXCR1 bindsIL-8 and GCP-2 with high affinity while CXCR2 binds all ELRCXCchemokines with high affinity.

Since CXC-chemokines promote the accumulation and activation ofneutrophils, CXC-chemokines have been implicated in a wide range ofacute and chronic inflammatory disorders including COPD, psoriasis andrheumatoid arthritis. (Baggiolini et al., FEBS Lett. 307, 97 (1992);Miller et al., Crit. Rev. Immunol. 12, 17 (1992); Oppenheim et al.,Annu. Rev. Immunol. 9, 617 (1991); Seitz et al., J. Clin. Invest. 87,463 (1991); Miller et al., Am. Rev. Respir. Dis. 146, 427 (1992);Donnely et al., Lancet 341, 643 (1998)).

ELRCXC chemokines, including IL-8, GROα, GROβ, GROγ, NAP-2, and ENA-78(Strieter et al. J. Biol. Chem. 270:27348-57, 1995), have also beenimplicated in the induction of tumor angiogenesis (new blood vesselgrowth). Angiogenic activity is due to ELRCXC-chemokine binding to, andactivation of CXCR2, and possibly CXCR1 for IL-8, expressed on thesurface of vascular endothelial cells (ECs) in surrounding vessels.

Many different types of tumors have been shown to produce ELRCXCchemokines. Chemokine production has been correlated with a moreaggressive phenotype (Inoue et al. Clin. Cancer Res. 6:2104-2119, 2000)and poor prognosis (Yoneda et. al. J. Nat. Cancer Inst. 90:447-454,1998). Chemokines are potent chemotactic factors and the ELRCXCchemokines, in particular, have been shown to induce EC chemotaxis.Thus, these chemokines are thought to induce chemotaxis of endothelialcells toward their site of production in the tumor. This may be acritical step in the induction of angiogenesis by the tumor. Inhibitorsof CXCR2 or dual inhibitors of CXCR2 and CXCR1 will inhibit theangiogenic activity of the ELRCXC chemokines and therefore block thegrowth of the tumor. This anti-tumor activity has been demonstrated forantibodies to IL-8 (Arenberg et al. J. Clin. Invest. 97:2792-2802,1996), ENA-78 (Arenberg et al., J. Clin. Invest. 102:465-72, 1998), andGROα (Haghnegandar et al., J Leukoc. Biology 67:53-62, 2000).

Therefore, there is a need in the art to find CXCR1/2 inhibitorcompounds and modulator compounds that can be used as pharmaceuticalcompounds. There remains a need for compounds that are capable ofmodulating activity at CXC-chemokine receptors. For example, conditionsassociated with an increase in IL-8 production (which is responsible forchemotaxis of neutrophil and T-cell subsets into the inflammatory siteand growth of tumors) would benefit by compounds that are inhibitors ofIL-8 receptor binding. The present disclosure was made to satisfy thisneed.

SUMMARY

The present disclosure further provides the compound having the formulaSX-682

The present disclosure further provides a pharmaceutical compositioncomprising the compound having the formula SX-682, or a pharmaceuticallyacceptable salt, or solvate thereof and a pharmaceutically acceptablecarrier. In certain embodiments, this disclosure provides SX-682 as anovel compound that is a CXC chemokine-modulator, pharmaceuticalcompositions comprising SX-682, and methods of treatment, prevention,inhibition, or amelioration of one or more diseases associated with CXCchemokine mediation using SX-682 and compositions disclosed herein.

The present disclosure provides a method for treating a disease ordisorder selected from the group consisting of pain (e.g., acute pain,acute inflammatory pain, chronic inflammatory pain, and neuropathicpain), acute inflammation, chronic inflammation, rheumatoid arthritis,psoriasis, atopic dermatitis, asthma, bronchopulmonary dysplasia, COPD,adult respiratory disease, arthritis, inflammatory bowel disease,Crohn's disease, ulcerative colitis, septic shock, endotoxic shock, gramnegative sepsis, toxic shock syndrome, stroke, ischemia reperfusioninjury, renal reperfusion injury, glomerulonephritis, thrombosis,Alzheimer's disease, graft vs. host reaction (i.e., graft-versus-hostdisease), allograft rejections (e.g., acute allograft rejection, andchronic allograft rejection), malaria, acute respiratory distresssyndrome, delayed type hypersensitivity reaction, atherosclerosis,cerebral ischemia, cardiac ischemia, osteoarthritis, multiple sclerosis,restinosis, angiogenesis, angiogenesis associated with tumor growth,osteoporosis, gingivitis, respiratory viruses, herpes viruses, hepatitisviruses, HIV, Kaposi's sarcoma associated virus (i.e., Kaposi'ssarcoma), meningitis, cystic fibrosis, pre-term labor, cough, pruritis,multi-organ dysfunction, trauma, strains, sprains, contusions, psoriaticarthritis, herpes, encephalitis, CNS vasculitis, traumatic brain injury,systemic tumors, CNS tumors, tumors dependent on angiogenesis forgrowth, leukopenia and neutropenia, chemotherapy-induced leukopenia andneutropenia, opportunistic infections associated with neutropenia orleukopenia, subarachnoid hemorrhage, post surgical trauma, interstitialpneumonitis, hypersensitivity, crystal induced arthritis, acutepancreatitis, chronic pancreatitis, acute alcoholic hepatitis,necrotizing enterocolitis, chronic sinusitis, angiogenic ocular disease,ocular inflammation, retinopathy of prematurity, diabetic retinopathy,macular degeneration with the wet type preferred, cornealneovascularization, polymyositis, vasculitis, acne, gastric ulcers,duodenal ulcers, celiac disease, esophagitis, glossitis, airflowobstruction, airway hyperresponsiveness (i.e., airway hyperreactivity),bronchiectasis, bronchiolitis, bronchiolitis obliterans, chronicbronchitis, cor pulmonae, dyspnea, emphysema, hypercapnea,hyperinflation, hypoxemia, hyperoxia-induced inflammations, hypoxia,surgical lung volume reduction, pulmonary fibrosis, pulmonaryhypertension, right ventricular hypertrophy, peritonitis associated withcontinuous ambulatory peritoneal dialysis (CAPD), granulocyticehrlichiosis, sarcoidosis, small airway disease, ventilation-perfusionmismatching, wheeze, colds, gout, alcoholic liver disease, lupus, burntherapy (i.e., the treatment of burns), periodontitis, cancer,transplant reperfusion injury, and early transplantation rejection(e.g., acute allograft rejection) in a patient in need of suchtreatment, comprising administering an effective amount of the compoundhaving the formula SX-682.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 illustrates SX-682 inhibition of CXCL8-mediated intracellularcalcium flux in isolated human neutrophils (legend ‘Human PMNs’), RBLcells stably transfected with CXCR1 (legend ‘CXCR1’), and RBL cellsstably transfected with CXCR2 (legend ‘CXCR2’). Mean (n=4, ±SE) IC₅₀values for SX-682 in each cell system are in parentheses in the legend.

FIG. 2 illustrates that inhibition of CXCL8-mediated intracellularcalcium flux in RBL cells stably transfected with CXCR1 is sustained forat least 12 hours after SX-682 washout.

FIG. 3 illustrates that inhibition of CXCL8-mediated intracellularcalcium flux in RBL cells stably transfected with CXCR2 is sustained forat least 12 hours after SX-682 washout.

FIG. 4 shows the effect of intravenous dosing of either SX-576 or SX-682on neutrophil influx in the ozone rat model of pulmonary inflammation.

FIG. 5 illustrates boronic acid containing CXCR1/CXCR2 inhibitors.

DETAILED DESCRIPTION OF ILLUSTRATIVE EMBODIMENTS Definitions

When any substituent or variable occurs more than one time in anymoiety, its definition on each occurrence is independent of itsdefinition at every other occurrence. Also, combinations of substituentsand/or variables are permissible only if such combinations result instable compounds.

Unless indicated otherwise, the following definitions apply throughoutthe present specification and claims. These definitions apply regardlessof whether a term is used by itself or in combination with other terms.For example, the definition of “alkyl” also applies to the “alkyl”portion of the defined term “alkoxy”.

“An effective amount” or a “therapeutically effective amount” means todescribe an amount of compound of the present disclosure or anotheragent effective to treat a mammal (e.g., a human) having a disease orCXC chemokine-mediated condition, and thus producing the desiredtherapeutic effect.

“At least one” means one or more (e.g., 1-3, 1-2, or 1).

“Composition” includes a product comprising the specified ingredients inthe specified amounts, as well as any product that results, directly orindirectly, from combination of the specified ingredients in thespecified amounts.

“In combination with” as used to describe the administration of SX-682with other medicaments in the methods of treatment of this invention,means-that SX-682 and the other medicaments are administeredsequentially or concurrently in separate dosage forms, or areadministered concurrently in the same dosage form.

“Mammal” means a human or other mammal, or means a human being.

“Patient” includes both human and other mammals, preferably human.

“Prodrug” denotes a compound that is a drug precursor which, uponadministration to a subject, undergoes chemical conversion by metabolicor chemical processes to yield SX-682 or a salt and/or solvate thereof.A discussion of pro-drugs is provided in T. Higuchi and V. Stella,Pro-drugs as Novel Delivery Systems, Volume 14 of the A.C.S. SymposiumSeries, and in Bioreversible Carriers in Drug Design, Edward B. Roche,ed., American Pharmaceutical Association and Pergamon Press, 1987, bothof which are incorporated herein by reference.

“Alkyl” is a saturated or unsaturated, straight or branched, hydrocarbonchain. In various embodiments, the alkyl group has 1-18 carbon atoms,i.e. is a C₁-C₁₈ group, or is a C₁-C₁₂ group, a C₁-C₆ group, or a C₁-C₄group. A lower alkyl group has 1-6 carbons. Independently, in variousembodiments, the alkyl group has zero branches (i.e., is a straightchain), one branch, two branches, or more than two branches.Independently, in one embodiment, the alkyl group is saturated. Inanother embodiment, the alkyl group is unsaturated. In variousembodiments, the unsaturated alkyl may have one double bond, two doublebonds, more than two double bonds, and/or one triple bond, two triplebonds, or more than two triple bonds. Alkyl chains may be optionallysubstituted with 1 substituent (i.e., the alkyl group ismono-substituted), or 1-2 substituents, or 1-3 substituents, or 1-4substituents, etc. The substituents may be selected from the groupconsisting of hydroxy, amino, alkylamino, boronyl, carboxy, nitro,cyano, and the like. When the alkyl group incorporates one or moreheteroatoms, the alkyl group is referred to herein as a heteroalkylgroup. When the substituents on an alkyl group are hydrocarbons, thenthe resulting group is simply referred to as a substituted alkyl. Invarious aspects, the alkyl group including substituents has less then25, 24, 23, 22, 21, 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, or7 carbons.

“Lower alkyl” means a group having about 1 to about 6 carbon atoms inthe chain which chain may be straight or branched. Non-limiting examplesof suitable alkyl groups include methyl, ethyl, n-propyl, isopropyl,n-butyl, t-butyl, n-pentyl, heptyl, nonyl, and decyl.

“Alkoxy” means an alkyl-O-group wherein alkyl is as defined above.Non-limiting examples of alkoxy groups include: methoxy, ethoxy,n-propoxy, isopropoxy, n-butoxy and heptoxy. The bond to the parentmoiety is through the ether oxygen.

“Alkoxyalkyl” means an alkoxy-alkyl-group in which the alkoxy and alkylare as previously described. Preferred alkoxyalkyl comprise a loweralkyl group. The bond to the parent moiety is through the alkyl.

“Alkylaryl” means an alkyl-aryl-group in which the alkyl and aryl are aspreviously described. Preferred alkylaryls comprise a lower alkyl group.The bond to the parent moiety is through the aryl.

“Aminoalkyl” means an NH₂-alkyl-group, wherein alkyl is as definedabove, bound to the parent moiety through the alkyl group.

“Aryl” (sometimes abbreviated “Ar”) is an aromatic carbocyclichydrocarbon ring system. The ring system may be monocyclic or fusedpolycyclic (e.g., bicyclic, tricyclic, etc.). In one embodiment, thearyl group is monocyclic, and is preferably a C₆ ring system, i.e. aphenyl ring is a preferred aryl ring, where preferred bicyclic arylrings are C₈-C₁₂, or C₉-C₁₀. A naphthyl ring, which has 10 carbon atoms,is a preferred polycyclic aryl ring. Unless otherwise indicated herein,the term “aryl” as used herein is meant to include aryl rings optionallysubstituted by one or more substituents selected from acyl (—C(O)—R),alkoxy (—O—R), alkyl, aryl, alkylamino (—N(H)—R and —N(R)R), alkylthio(—S—R), amino (—NH₂), azido (—N₃), boronyl (—B(R)R or —B(OH)₂ or—B(OR)₂), carboxy (—C(O)—OH), alkoxycarbonyl (—C(O)—OR), aminocarbonyl(—C(O)—NH₂), aminosulfonyl (—S(O)₂—NH₂), alkylaminocarbonyl (—C(O)—N(H)Rand —C(O)—N(R)R), cyano, halo (fluoro, bromo, chloro, iodo), haloalkyl,haloalkoxy, heterocyclyl, heteroalkyl, hydroxyl (—OH), acyloxy(—O—C(O)—R), ketone (—C(O)—R), substituted halomethylketone(—C(O)—CH—X—, where m+n=3, X═F, Cl, Br), mercapto (—SH and —S—R) andnitro (—NO₂) where each R group is an alkyl group having less than about12 carbons, preferably where the R group is a lower alkyl group.Non-limiting examples of suitable aryl groups include: phenyl, naphthyl,indenyl, tetrahydronaphthyl, indanyl, anthracenyl, and fluorenyl.

“Arylalkyl” refers to an alkyl group as defined substituted by one ormore aryl groups as defined below. Phenyl and naphthyl are preferredaryl groups in an arylalkyl group. A preferred alkyl group is methyl, sothat a preferred arylalkyl group is benzyl or benzyl having one or moresubstituents on the phenyl ring. Unless otherwise indicated, the term“arylalkyl” as used herein is meant to include arylalkyl groups whereinthe aryl ring therein is optionally substituted by one or moresubstituents selected from acyl (—C(O)—R), alkoxy (—O—R), alkyl, aryl,alkylamino (—N(H)—R and —N(R)R), alkylthio (—S—R), amino (—NH₂), azido(—N₃), boronyl (—B(R)R or —B(OH)₂ or —B(OR)₂), carboxy (—C(O)—OH),alkoxycarbonyl (—C(O)—OR), aminocarbonyl (—C(O)—NH₂), aminosulfonyl(—S(O)₂—NH₂), alkylaminocarbonyl (—C(O)—N(H)R and —C(O)—N(R)R), cyano,halo (fluoro, bromo, chloro, iodo), haloalkyl, haloalkoxy, heterocyclyl,heteroalkyl, hydroxyl (—OH), acyloxy (—O—C(O)—R), ketone (—C(O)—R),substituted halomethylketone (—C(O)—CH_(m)X_(n), where m+n=3, X═F, Cl,Br), mercapto (—SH and —S—R) and nitro (—NO₂) where each R is an alkylgroup having less than about 12 carbons, preferably where the R group isa lower alkyl group.

“Arylalkyl” means an aryl-alkyl-group in which the aryl and alkyl are aspreviously described. Preferred arylalkyls comprise a lower alkyl group.Non-limiting examples of suitable aralkyl groups include benzyl,2-phenethyl and naphthalenylmethyl. The bond to the parent moiety isthrough the alkyl.

“Aryloxy” means an aryl-O-group in which the aryl group is as previouslydescribed. Non-limiting examples of suitable aryloxy groups includephenoxy and naphthoxy. The bond to the parent moiety is through theether oxygen.

“Carboxyalkyl” means an HOOC-alkyl-group, wherein alkyl is as definedabove, bound to the parent moiety through the alkyl group.

“Chemokine” means a protein molecule involved in chemotaxis.

A “chemokine-mediated disease” means a disease of which at least oneelement or cause is related to the regulation of a CXC chemokine.

“Commercially available chemicals” and the chemicals used in theExamples set forth herein may be obtained from standard commercialsources, where such sources include, for example, Acros Organics(Pittsburgh, Pa.), Sigma-Adrich Chemical (Milwaukee, Wis.), AvocadoResearch (Lancashire, U.K.), Bionet (Cornwall, U.K.), Boron Molecular(Research Triangle Park, N.C.), Combi-Blocks (San Diego, Calif.),Eastman Organic Chemicals, Eastman Kodak Company (Rochester, N.Y.),Fisher Scientific Co. (Pittsburgh, Pa.), Frontier Scientific (Logan,Utah), ICN Biomedicals, Inc. (Costa Mesa, Calif.), Lancaster Synthesis(Windham, N.H.), Maybridge Chemical Co. (Cornwall, U.K.), PierceChemical Co. (Rockford, Ill.), Riedel de Haen (Hannover, Germany),Spectrum Quality Product, Inc. (New Brunswick, N.J.), TCI America(Portland, Oreg.), and Wako Chemicals USA, Inc. (Richmond, Va.).

“Compounds described in the chemical literature” may be identifiedthrough reference books and databases directed to chemical compounds andchemical reactions, as known to one of ordinary skill in the art.Suitable reference books and treatise that detail the synthesis ofreactants useful in the preparation of compounds disclosed herein, orprovide references to articles that describe the preparation ofcompounds disclosed herein, include for example, “Synthetic OrganicChemistry”, John Wiley and Sons, Inc. New York; S. R. Sandler et al,“Organic Functional Group Preparations,” 2^(nd) Ed., Academic Press, NewYork, 1983; H. O. House, “Modern Synthetic Reactions,” 2^(nd) Ed., W. A.Benjamin, Inc. Menlo Park, Calif., 1972; T. L. Glichrist, “HeterocyclicChemistry,” 2^(nd) Ed. John Wiley and Sons, New York, 1992; J. March,“Advanced Organic Chemistry: reactions, Mechanisms and Structure,”5^(th) Ed., Wiley Interscience, New York, 2001; Specific and analogousreactants may also be identified through the indices of known chemicalsprepared by the Chemical Abstract Service of the American ChemicalSociety, which are available in most public and university libraries, aswell as through online databases (the American Chemical Society,Washington, D.C. www.acs.org may be contacted for more details).Chemicals that are known but not commercially available in catalogs maybe prepared by custom chemical synthesis houses, where many of thestandard chemical supply houses (e.g. those listed above) provide customsynthesis services.

“Cycloalkyl” means a non-aromatic mono- or multicyclic ring systemcomprising about 3 to about 10 carbon atoms, preferably about 5 to about10 carbon atoms. Preferred cycloalkyl rings contain about 5 to about 7ring atoms. A multicyclic cycloalkyl substituent may include fused,Spiro, or bridged ring structures. Non-limiting examples of suitablemonocyclic cycloalkyls include cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, cycloheptyl and the like. Non-limiting examples of suitablemulticyclic cycloalkyls include 1-decalin, norbornyl, adamantly and thelike. Cycloalkyl substituents may be substituted or unsubstituted. Inone embodiment, the cycloalkyl is unsubstituted. In another embodiment,the cycloalkyl is substituted with, e.g., 1 substituent (i.e., thecycloalkyl group is mono-substituted), or 1-2 substituents, or 1-3substituents, or 1-4 substituents, etc. In one embodiment, thesubstituents that may be present on the cycloalkyl aliphatic ring areselected from acyl (—C(O)—R), alkoxy (—O—R), alkyl, aryl, alkylamino(—N(H)—R and —N(R)R), alkylthio (—S—R), amino (—NH₂), azido (—N₃),boronyl (—B(R)R or —B(OH)₂ or —B(OR)₂), carboxy (—C(O)—OH),alkoxycarbonyl (—C(O)—OR), aminocarbonyl (—C(O)—NH₂), aminosulfonyl(—S(O)₂—NH₂), alkylaminocarbonyl (—C(O)—N(H)R and —C(O)—N(R)R), cyano,halo (fluoro, bromo, chloro, iodo), haloalkyl, haloalkoxy, heterocyclyl,heteroalkyl, hydroxyl (—OH), acyloxy (—O—C(O)—R), ketone (—C(O)—R),substituted halomethylketone (—C(O)—CH_(m)X_(n), where m+n=3, X═F, Cl,Br), mercapto (—SH and —S—R) and nitro (—NO₂) In one aspect the R groupin the above substituents is an alkyl group having less than about 12carbons, while in another aspect the R group is a lower alkyl group.

“Cycloalkylalkyl” means a cycloalkyl group bound to the parent moietythrough an alkyl group. Non-limiting examples include: cyclopropylmethyland cyclohexylmethyl.

“Cycloalkylaryl” means a cycloalkyl group bound to the parent moietythrough an aryl group. Non-limiting examples include: cyclopropylphenyland cyclohexylphenyl.

“Effective amount” or “therapeutically effective amount” is meant todescribe an amount of compound or a composition of the presentdisclosure effective in decreasing or increasing (i.e., modulating) theaction of a CXC chemokine at a CXC chemokine receptor and thus producingthe desired therapeutic effect in a suitable patient.

“Fluoroalkoxy” means an alkoxy group as defined above wherein one ormore hydrogen atoms on the alkoxy is or are replaced by a fluoro group.

“Fluoroalkyl” means an alkyl group as defined above wherein one or morehydrogen atoms on the alkyl are replaced by a fluoro group.

“Halo” means fluoro, chloro, bromo, or iodo groups. Preferred arefluoro, chloro or bromo, and more preferred are fluoro and chloro.

“Halogen” means fluorine, chlorine, bromine, or iodine. Preferred arefluorine, chlorine and bromine.

“Heteroalkyl” is a saturated or unsaturated, straight or branched, chaincontaining carbon and at least one heteroatom. The heteroalkyl groupmay, in various embodiments, have on heteroatom, or 1-2 heteroatoms, or1-3 heteroatoms, or 1-4 heteroatoms. In one aspect the heteroalkyl chaincontains from 1 to 18 (i.e., 1-18) member atoms (carbon andheteroatoms), and in various embodiments contain 1-12, or 1-6, or 1-4member atoms. Independently, in various embodiments, the heteroalkylgroup has zero branches (i.e., is a straight chain), one branch, twobranches, or more than two branches. Independently, in one embodiment,the heteroalkyl group is saturated. In another embodiment, theheteroalkyl group is unsaturated. In various embodiments, theunsaturated heteroalkyl may have one double bond, two double bonds, morethan two double bonds, and/or one triple bond, two triple bonds, or morethan two triple bonds. Heteroalkyl chains may be substituted orunsubstituted. In one embodiment, the heteroalkyl chain isunsubstituted. In another embodiment, the heteroalkyl chain issubstituted. A substituted heteroalkyl chain may have 1 substituent(i.e., by monosubstituted), or may have 1-2 substituents, or 1-3substituents, or 1-4 substituents, etc. Exemplary heteroalkylsubstituents include esters (—C(O)—O—R) and carbonyls (—C(O)—).

“Heterocyclic” (or “heterocycloalkyl” or “heterocyclyl”) refers to anon-aromatic saturated monocyclic or multicyclic ring system comprising3 to 10 ring atoms (e.g., 3 to 7 ring atoms), or 5 to 10 ring atoms, inwhich one or more of the atoms in the ring system is an element otherthan carbon, for example nitrogen, oxygen or sulfur, alone or incombination. There are no adjacent oxygen and/or sulfur atoms present inthe ring system. Examples of heterocyclics or heterocycloalkyls includerings having 5 to 6 ring atoms. The prefix aza, oxa or thia before theheterocyclic or heterocycloalkyl root name means that at least anitrogen, oxygen or sulfur atom, respectively, is present as a ringatom. The nitrogen or sulfur atom of the heterocyclic orheterocycloalkyl can be optionally oxidized to the correspondingN-oxide, S-oxide or S,S-dioxide. Any nitrogen atoms may be optionallyquaternized. Non-limiting examples of monocyclic heterocyclic orheterocycloalkyl rings include: piperidyl, pyrrolidinyl, piperazinyl,morpholinyl, thiomorpholinyl, thiazolidinyl, 1,3-dioxolanyl,1,4-dioxanyl, tetrahydrofuranyl, tetrahydrothiophen-yl, andtetrahydrothiopyranyl The heterocyclyl may be unsubstituted orsubstituted. In one embodiment, the heterocyclyl is unsubstituted. Inanother embodiment, the heterocyclyl is substituted. The substitutedheterocyclyl ring may contain 1 substituent, or 1-2 substituents, or 1-3substituents, or 1-4 substituents, etc. In one embodiment, thesubstituents that may be present on the heterocyclyl ring are selectedfrom acyl (—C(O)—R), alkoxy (—O—R), alkyl, aryl, alkylamino (—N(H)—R and—N(R)R), alkylthio (—S—R), amino (—NH₂), azido (—N₂), boronyl (—B(R)R or—B(OH)₂ or —B(OR)₂), carboxy (—C(O)—OH), alkoxycarbonyl (—C(O)—OR),aminocarbonyl (—C(O)—NH₂), aminosulfonyl (—S(O)₂—NH₂),alkylaminocarbonyl (—C(O)—N(H)R and —C(O)—N(R)R), cyano, halo (fluoro,bromo, chloro, iodo), haloalkyl, haloalkoxy, heterocyclyl, heteroalkyl,hydroxyl (—OH), acyloxy (—O—C(O)—R), ketone (—C(O)—R), substitutedhalomethylketone (—C(O)—CH_(m)X_(n), where m+n=3, X═F, Cl, Br), mercapto(—SH and —S—R) and nitro (—NO₂) In one aspect, the R group which is, oris part of the substituent attached to the heterocyclic ring is an alkylgroup having less than about 12 carbons, while in another aspect the Rgroup is a lower alkyl group.

“Heterocycloalkylalkyl” means a heterocycloalkyl-alkyl group, whereinsaid heterocycloalkyl and said alkyl are as defined above, bound to aparent moiety through the alkyl group.

“Heteroaryl” means an aromatic monocyclic or multicyclic ring systemcomprising 5 to 14 ring atoms, or 5 to 10 ring atoms, in which one ormore of the ring atoms is an element other than carbon, for examplenitrogen, oxygen or sulfur, alone or in combination. Heteroaryls cancontain 5 to 6 ring atoms. The prefix aza, oxa or thio before theheteroaryl root name means that at least a nitrogen, oxygen or sulfuratom respectively, is present as a ring atom. A nitrogen atom of aheteroaryl can be optionally oxidized to the corresponding N-oxide. Anynitrogen atoms may be optionally quaternized. Non-limiting examples ofheteroaryls include: pyridyl, pyrazinyl, furanyl, thienyl, pyrimidinyl,isoxazolyl, isothiazolyl, oxazolyl, thiazolyl, pyrazolyl, furazanyl,pyrrolyl, pyrazolyl, triazolyl, 1,2,4-thiadiazolyl, pyrazinyl,pyridazinyl, quinoxalinyl, phthalazinyl, imidazo[1,2-a]pyridinyl,imidazo[2,1-b]thiazolyl, benzofurazanyl, indolyl, azaindolyl,benzimidazolyl, benzothienyl, quinolinyl, imidazolyl, thienopyridyl,quinazolinyl, thienopyrimidyl, pyrrolopyridyl, imidazopyridyl,isoquinolinyl, benzoazaindolyl, 1,2,4-triazinyl, and benzothiazolyl. Theheteroaryl may be unsubstituted or substituted. In one embodiment, theheteroaryl is unsubstituted. In another embodiment, the heteroaryl issubstituted. The substituted heteroaryl ring may contain 1 substituent,or 1-2 substituents, or 1-3 substituents, or 1-4 substituents, etc. Inone embodiment, the substituents that may be present on the heteroarylring are selected from acyl (—C(O)—R), alkoxy (—O—R), alkyl, aryl,alkylamino (—N(H)—R and —N(R)R), alkylthio (—S—R), amino (—NH₂), azido(—N₂), boronyl (—B(R)R or —B(OH)₂ or —B(OR)₂), carboxy (—C(O)—OH),alkoxycarbonyl (—C(O)—OR), aminocarbonyl (—C(O)—NH₂), aminosulfonyl(—S(O)₂—NH₂), alkylaminocarbonyl (—C(O)—N(H)R and —C(O)—N(R)R), cyano,halo (fluoro, bromo, chloro, iodo), haloalkyl, haloalkoxy, heterocyclyl,heteroalkyl, hydroxyl (—OH), acyloxy (—O—C(O)—R), ketone (—C(O)—R),substituted halomethylketone (—C(O)—CH_(m)X_(n), where m+n=3, X═F, Cl,Br), mercapto (—SH and —S—R) and nitro (—NO₂) In one aspect, the R groupwhich is, or is part of the substituent attached to the heteroaryl ringis an alkyl group having less than about 12 carbons, while in anotheraspect the R group is a lower alkyl group.

“Heteroarylkyl” or “heteroarylalkyl” means a heteroaryl-alkyl-group, inwhich the heteroaryl and alkyl are as previously described. Preferredheteroaralkyls can contain a lower alkyl group. Non-limiting examples ofsuitable aralkyl groups include pyridylmethyl, 2-(furan-3-yl)ethyl andquinolin-3-ylmethyl. The bond to the parent moiety is through the alkyl.

“Hydroxyalkyl” means an HO-alkyl-group, in which alkyl is previouslydefined. Preferred hydroxyalkyls contain lower alkyl. Non-limitingexamples of suitable hydroxyalkyl groups include hydroxymethyl and2-hydroxyethyl.

“Hydrate” is a solvate wherein the solvent molecule is H₂O.

“Solvate” means a physical association of a compound of this disclosurewith one or more solvent molecules. This physical association involvesvarying degrees of ionic and covalent bonding, including hydrogenbonding. In certain instances the solvate will be capable of isolation,for example when one or more solvent molecules are incorporated in thecrystal lattice of the crystalline solid. “Solvate” encompasses bothsolution-phase and isolatable solvates. Non-limiting examples ofsuitable solvates include ethanolates, methanolates, and the like.

Examples of “disease modifying antirheumatic drugs” (i.e., DMARDs)include, for example, methotrexate, aminopterin, sulfasalzine,leflunomide, TNFα directed agents (e.g., infliximab, etanercept, andadalimumab), IL-1 directed agents (e.g., anakinra) B cell directedagents (e.g., rituximab), T cell directed agents (e.g., alefacept,efalizumab, and CTLA4-1g), TNFα-converting enzyme inhibitors,interleukin-1 converting enzyme is inhibitors, and p38 kinaseinhibitors.

The term “other classes of compounds indicated for the treatment ofrheumatoid arthritis”, as used herein, unless indicated otherwise,means: compounds selected from the group consisting of: IL-1 directedagents (e.g., anakinra); B cell directed agents (e.g., rituximab); Tcell directed agents (e.g., alefacept, efalizumab, and CTLA4-1g),TNFα-converting enzyme inhibitors, interleukin-1 converting enzymeinhibitors, and p38 kinase inhibitors.

The compound having the formula SX-682 forms salts that are also withinthe scope of this disclosure. Reference to the compound having theformula SX-682 herein is understood to include reference to saltsthereof, unless otherwise indicated. The term “salt(s)”, as employedherein, denotes acidic salts formed with inorganic and/or organic acids,as well as basic salts formed with inorganic and/or organic bases. Thesalts can be pharmaceutically acceptable (i.e., non-toxic,physiologically acceptable) salts, although other salts are also useful.Salts of the compound having the formula SX-682 may be formed, forexample, by reacting it with an amount of acid or base, such as anequivalent amount, in a medium such as one in which the saltprecipitates or in an aqueous medium followed by lyophilization.

Exemplary acid addition salts include acetates, adipates, alginates,ascorbates, aspartates, benzoates, benzenesulfonates, bisulfates,borates, butyrates, citrates, camphorates, camphorsulfonates,cyclopentanepropionates, digluconates, dodecylsulfates,ethanesulfonates, fumarates, glucoheptanoates, glycerophosphates,hemisulfates, heptanoates, hexanoates, hydrochlorides, hydrobromides,hydroiodides, 2-hydroxyethanesulfonates, lactates, maleates,methanesulfonates, 2-napthalenesulfonates, nicotinates, nitrates,oxalates, pectinates, persulfates, 3-phenylpropionates, phosphates,picrates, pivalates, propionates, salicylates, succinates, sulfates,sulfonates (such as those mentioned herein), tartarates, thiocyanates,toluenesulfonates (also known as tosylates) undecanoates, and the like.Additionally, acids which are generally considered suitable for theformation of pharmaceutically useful salts from basic pharmaceuticalcompounds are discussed, for example, by S. Berge et al, J.Pharmaceutical Sciences (1977) 66(1)1-19; P. Gould, International J.Pharmaceutics (1986) 33 201-217; Anderson et al, The Practice ofMedicinal Chemistry (1996), Academic Press, New York; and in The OrangeBook (Food & Drug Administration, Washington, D.C. on their website).These disclosures are incorporated herein by reference herein.

Exemplary basic salts include ammonium salts, alkali metal salts such assodium, lithium, and potassium salts, alkaline earth metal salts such ascalcium and magnesium salts, salts with organic bases (for example,organic amines) such as benzathines, dicyclohexylamines, hydrabamines(formed with N,N-bis(dehydroabietyl)ethylenediamine),N-methyl-D-glucamines, N-methyl-D-glucamides, t-butyl amines, and saltswith amino acids such as arginine, lysine and the like. Basicnitrogen-containing groups may be quarternized with agents such as loweralkyl halides (e.g., methyl, ethyl, propyl, and butyl chlorides,bromides and iodides), dialkyl sulfates (e.g., dimethyl, diethyl,dibutyl, and diamyl sulfates), long chain halides (e.g., decyl, lauryl,myristyl, and stearyl chlorides, bromides and iodides), arylalkylhalides (e.g., benzyl and phenethyl bromides), and others.

All such acid and base salts are intended to be pharmaceuticallyacceptable salts within the scope of the disclosure and all acid andbase salts are considered equivalent to the free forms of thecorresponding compounds for purposes of the disclosure.

The compound having the formula SX-682 can exist in unsolvated andsolvated forms, including hydrated forms. In general, the solvatedforms, with pharmaceutically acceptable solvents such as water, ethanoland the like, are equivalent to the unsolvated forms for the purposes ofthis disclosure.

The compound having the formula SX-682 and salts, solvates and prodrugsthereof, may exist in their tautomeric form (for example, as an amide orimino ether). All such tautomeric forms are contemplated herein as partof the present disclosure.

Also within the scope of the present disclosure are polymorphs of thecompounds of this disclosure (i.e., polymorphs of the compound havingthe formula SX-682 are within the scope of this disclosure).

Prodrugs of the compound having the formula SX-682 or pharmaceuticallyacceptable salts or solvates thereof are within the scope of thisdisclosure.

All stereoisomers (for example, geometric isomers, optical isomers andthe like) of the compound having the formula SX-682 (including those ofthe salts, solvates and prodrugs of the compounds as well as the saltsand solvates of the prodrugs), such as those which may exist due toasymmetric carbons on various substituents, including enantiomeric forms(which may exist even in the absence of asymmetric carbons), rotamericforms, atropisomers, and diastereomeric forms, are contemplated withinthe scope of this disclosure. Individual stereoisomers of the compoundsof this disclosure may, for example, be substantially free of otherisomers, or may be admixed, for example, as racemates or with all other,or other selected, stereoisomers. The chiral centers of the compoundsherein can have the S or R configuration as defined by the IUPAC 1974Recommendations. The use of the terms “salt”, “solvate”, “prodrug” andthe like, is intended to equally apply to the salt, solvate and prodrugof enantiomers, stereoisomers, rotamers, tautomers, racemates orprodrugs of the disclosed compounds.

Classes of compounds that can be used as the chemotherapeutic agent(antineoplastic agent) include: alkylating agents, antimetabolites,natural products and their derivatives, hormones and steroids (includingsynthetic analogs), and synthetics. Examples of compounds within theseclasses are given below.

Alkylating agents (including nitrogen mustards, ethyleniminederivatives, alkyl sulfonates, nitrosoureas and triazenes): Uracilmustard, Chlormethine, Cyclophosphamide, Ifosfamide, Melphalan,Chlorambucil, Pipobroman, Triethylene-melamine,Triethylenethiophos-phoramine, Busulfan, Carmustine, Lomustine,Streptozocin, Dacarbazine, and Temozolomide.

Antimetabolites (including folic acid antagonists, pyrimidine analogs,purine analogs and adenosine deaminase inhibitors): Methotrexate,Aminopterin, 5-Fluorouracil, Floxuridine, Cytarabine, 6-Mercaptopurine,6-Thioguanine, Fludarabine phosphate, Pentostatine, and Gemcitabine.

Natural products and their derivatives (including vinca alkaloids,antitumor antibiotics, enzymes, lymphokines and epipodophyllotoxins):Vinblastine, Vincristine, Vindesine, Bleomycin, Dactinomycin,Daunorubicin, Doxorubicin, Epirubicin, Idarubicin, paclitaxel (Taxol®),Mithramycin, Deoxycoformycin, Mitomycin-C, L-Asparaginase, Interferons(especially IFN-γ), etoposide, and Teniposide.

Hormones and steroids (including synthetic analogs):17α-Ethinylestradiol, Diethylstilbestrol, Testosterone, Prednisone,Fluoxymesterone, Dromostanolone propionate, Testolactone,Megestrolacetate, Tamoxifen, Methylprednisolone, Methyltestosterone,Prednisolone, Triamcinolone, Chlorotrianisene, Hydroxyprogesterone,Aminoglutethimide, Estramustine, Medroxyprogesteroneacetate, Leuprolide,Flutamide, Toremifene, Zoladex.

Synthetics (including inorganic complexes such as platinum coordinationcomplexes): Cisplatin, Carboplatin, Hydroxyurea, Amsacrine,Procarbazine, Mitotane, Mitoxantrone, Levamisole, andHexamethylmelamine.

Methods for the safe and effective administration of most of thesechemotherapeutic agents are known to those skilled in the art. Inaddition, their administration is described in the standard literature.For example, the administration of many of the chemotherapeutic agentsis described in the “Physicians' Desk Reference” (PDR), e.g., 2008edition (Thomson P D R, Montvale, N.J. 07645-1742, 25 USA); thedisclosure of which is incorporated herein by reference herein.

As used herein, a microtubule affecting agent is a compound thatinterferes with cellular mitosis, i.e., having an anti-mitotic effect,by affecting microtubule formation and/or action. Such agents can be,for instance, microtubule stabilizing agents or agents that disruptmicrotubule formation.

Microtubule affecting agents useful in this disclosure are well known tothose of skilled in the art and include, but are not limited toallocolchicine (NSC 406042), Halichondrin B (NSC 609395), colchicine(NSC 757), colchicine derivatives (e.g., NSC 33410), dolastatin 10 (NSC376128), maytansine (NSC 153858), rhizoxin (NSC 332598), paclitaxel(Taxol, NSC 125973), Taxol derivatives (e.g., derivatives (e.g., NSC608832), thiocolchicine (NSC 361792), trityl cysteine (NSC 83265),vinblastine sulfate (NSC 49842), vincristine sulfate (NSC 67574),epothilone A, epothilone, and discodermolide (see Service, (1996)Science, 274:2009) estramustine, nocodazole, MAP4, and the like.Examples of such agents are also described in the scientific and patentliterature, see, e.g., Bulinski (1997) J. Cell Sci. 110:3055-3064; Panda(1997) Proc. Natl. Acad. Sci. USA 94:10560-10564; Muhlradt (1997) CancerRes. 57, 3344-3346; Nicolaou (1997) Nature 387:268-272; Vasquez (1997)Mol. Biol. Cell. 8:973-985; Panda (1996) J. Biol. Chem. 271:29807-29812.

Particularly, agents can be compounds with paclitaxel-like activity.These include, but are not limited to paclitaxel and paclitaxelderivatives (paclitaxel-like compounds) and analogues. Paclitaxel andits derivatives are available commercially. In addition, methods ofmaking paclitaxel and paclitaxel derivatives and analogues are wellknown to those of skilled in the art (see, e.g., U.S. Pat. Nos.5,569,729; 5,565,478; 5,530,020; 5,527,924; 5,508,447; 5,489,589;5,488,116; 5,484,809; 5,478,854; 5,478,736; 5,475,120; 5,468,769;5,461,169; 5,440,057; 5,422,364; 5,411,984; 5,405,972; and 5,296,506,the disclosures of which are incorporated by reference herein).

Additional microtubule affecting agents can be assessed using one ofmany such assays known in the art, e.g., a semiautomated assay whichmeasures the tubulin-polymerizing activity of paclitaxel analogs incombination with a cellular assay to measure the potential of thesecompounds to block cells in mitosis (see Lopes (1997) Cancer Chemother.Pharmacol. 41:37-47).

Therapeutic Activity

Modulators of neutrophil activity can have great therapeutic benefit ina number of indications. In disease states characterized by animproperly heightened neutrophil response, an inhibitor of neutrophilactivity would be indicated. In patients suffering from, for exampleneutropenia, a neutrophil agonist or activator has clinical benefit. Invivo evaluation of two lead compounds SX-517 and SX-576 in the murineair-pouch model of inflammation, revealed that both inhibitory andagonist activity on neutrophils were achieved, depending on the dosegiven.

Methods of Treatment

One embodiment is directed to a pharmaceutical composition comprisingSX-682 or a pharmaceutically acceptable salt or solvate thereof, incombination with a pharmaceutically acceptable carrier.

The methods of treatment of this disclosure are advantageous in treatingdiseases where the ELR-CXC chemokine binds to CXCR2. Another embodimentof the disclosure is directed to a method of treating CXCR1/2 chemokinemediated diseases in a patient in need of such treatment comprisingadministering to the patient a therapeutically effective amount ofcompound SX-682, or a pharmaceutically acceptable salt or solvatethereof.

Another embodiment of the disclosure is a method of treating CXCR1/2chemokine mediated diseases in a patient in need thereof comprisingadministering to the patient (a) an effective amount of the compoundhaving the formula SX-682, or a pharmaceutically acceptable salt orsolvate thereof, concurrently or sequentially with (b) at least oneadditional agent, drug, medicament, antibody and/or inhibitor useful forthe treatment of CXCR1/2 chemokine mediated diseases. Examples of theadditional medicament, drug or agent include, but are not limited to,disease modifying antirheumatic drugs; nonsteroidal antiinflammatorydrugs (NSAIDs); COX-2 selective inhibitors; COX-1 inhibitors;immunosuppressives; steroids; biological response modifiers; and otheranti-inflammatory agents or therapeutics useful for the treatment ofCXCR1/2 chemokine mediated diseases.

Another embodiment of the method of treating a CXCR1/2 chemokinemediated disease is administering (a) a therapeutically effective amountof the compound having the formula SX-682, or a pharmaceuticallyacceptable salt or solvate thereof, concurrently or sequentially with(b) at least one medicament selected from the group consisting of:disease modifying antirheumatic drugs; nonsteroidal anti-inflammatorydrugs; COX-2 selective inhibitors; COX-1 inhibitors; immunosuppressives;steroids; biological response modifiers; and other anti-inflammatoryagents or therapeutics useful for the treatment of CXCR1 and/or CXCR2chemokine mediated diseases.

Another embodiment of this disclosure is a method for treating cancer ina patient in need of such treatment, the method comprises administeringto said patient a therapeutically effective amount of the compoundhaving the formula SX-682, or a pharmaceutically acceptable salt orsolvate thereof. Another embodiment of this disclosure is a method fortreating cancer comprising administering to the patient a therapeuticamount of the compound having the formula SX-682, or a pharmaceuticallyacceptable salt or solvate thereof, concurrently or sequentially with(a) at least one antineoplastic agent selected from the group consistingof: (1) gemcitabine, (2) paclitaxel, (3) 5-fluorouracil (5-FU), (4)cyclo-phosphamide, (5) temozolomide and (6) vincristine or (b) at leastone agent selected from the group consisting of (1) microtubuleaffecting agents, (2) antineoplastic agents, (3) anti-angiogenesisagents, (4) VEGF receptor kinase inhibitors, (5) antibodies against theVEGF receptor, (6) interferon, and (7) radiation.

Another embodiment of this disclosure is a method for treating asthma ina patient in need of such treatment the method comprising administeringto the patient a therapeutically effective amount of the compound havingthe formula SX-682, or a pharmaceutically acceptable salt or solvatethereof. Another embodiment of this disclosure is a method for treatinga pulmonary disease (e.g., COPD, asthma, or cystic fibrosis), in apatient in need of such treatment, the method comprising administeringto the patient a therapeutically effective amount of: (a) the compoundhaving the formula SX-682, or a pharmaceutically acceptable salt orsolvate thereof, concurrently or sequentially with (b) at least onecompound selected from the group consisting of: glucocorticoids,5-lipoxygenase inhibitors, beta-2 adrenoceptor agonists, muscarinic M1antagonists, muscarinic M3 antagonists, muscarinic M2 agonists, NK3antagonists, LTB4 antagonists, cysteinyl leukotriene antagonists,bronchodilators, PDE4 inhibitors, PDE inhibitors, elastase inhibitors,MMP inhibitors, phospholipase A2 inhibitors, phospholipase D inhibitors,histamine H1 antagonists, histamine H3 antagonists, dopamine agonists,adenosine A2 agonists, NK1 and NK2 antagonists, GABA-β agonists,nociceptin agonists, expectorants, mucolytic agents, decongestants,antioxidants, anti-IL-8 antibodies, anti-IL-5 antibodies, anti-IgEantibodies, anti-TNF antibodies, IL-10, adhesion molecule inhibitors,and growth hormones.

Another embodiment of this disclosure is a method for treating multiplesclerosis, comprising administering to the patient: (a) atherapeutically effective amount of the compound having the formulaSX-682, or a pharmaceutically acceptable salt or solvate thereof,concurrently or sequentially with (b) a therapeutically effective amountof at least one compound selected from the group consisting of:glatiramer acetate, glucocorticoids, methotrexate, azothioprine,mitoxantrone, and CB2-selective inhibitors.

Another embodiment of this disclosure is a method of treating multiplesclerosis comprising concurrent or sequential administration of atherapeutically effective amount of: (a) the compound having the formulaSX-682, or a pharmaceutically acceptable salt or solvate thereof, and(b) at least one compound selected from the group consisting of:methotrexate, cyclosporin, leflunimide, sulfasalazine, β-methasone,β-interferon, glatiramer acetate, prednisone, etonercept, andinfliximab.

Another embodiment of this disclosure is a method for treatingrheumatoid arthritis in a patient in need of such treatment comprisingadministering to said patient a therapeutically effective amount of thecompound having the formula SX-682, or a pharmaceutically acceptablesalt or solvate thereof.

Another embodiment of this disclosure is a method for treatingrheumatoid arthritis in a patient in need of such treatment comprisingadministering to said patient a therapeutically effective amount of thecompound having the formula SX-682, or a pharmaceutically acceptablesalt or solvate thereof, in combination with at least one compoundselected from the group consisting of COX-2 inhibitors, COX-1inhibitors, immunosuppressives (e.g., methotrexate, aminopterin,cyclosporin, leflunimide and sulfasalazine), steroids (e.g.,betamethasone, cortisone and dexamethasone), PDE 4 inhibitors,anti-TNF-alpha compounds, MMP inhibitors, glucocorticoids, chemokineinhibitors, CB2-selective agents, and other classes of compoundsindicated for the treatment of rheumatoid arthritis.

Another embodiment of this disclosure is a method for treating strokeand ischemia reperfusion injury in a patient in need of such treatmentthe method comprising administering to the patient a therapeuticallyeffective amount of: (a) the compound having the formula SX-682, or apharmaceutically acceptable salt or solvate thereof, concurrently orsequentially with (b) at least one compound selected from the groupconsisting of: thrombolitics (e.g., tenecteplase, TPA, alteplase),antiplatelet agents (e.g., gpllb/llla), antagonists (e.g., abciximab andeftiifbatide), anticoagulants (e.g., heparin), and other compoundsindicated for the treatment of stroke and ischemia reperfusion injury.

Another embodiment of this disclosure is a method for treating strokeand ischemia reperfusion injury in a patient in need of such treatmentthe method comprising administering to the patient a therapeuticallyeffective amount of: (a) the compound having the formula SX-682, or apharmaceutically acceptable salt or solvate thereof concurrently orsequentially with (b) at least one compound selected from the groupconsisting of: tenecteplase, TPA, alteplase, abciximab, eftiifbatide,and heparin.

Another embodiment of this disclosure is a method for treating psoriasisin a patient in need of such treatment, the method comprisingadministering to the patient a therapeutically effective amount of: a)the compound having the formula SX-682, or a pharmaceutically acceptablesalt or solvate thereof, concurrently or sequentially with (b) at leastone compound selected from the group consisting of: immunosuppressives(e.g., methotrexate, aminopterin, cyclosporin, efalizumab, alefacept,leflunimide and sulfasalazine), steroids (e.g., β-methasone) andanti-TNFα compounds (e.g., etonercept and infliximab).

This disclosure also provides a method for treating CXCR1/2 mediateddisease or condition selected from the group consisting of: pain (e.g.,acute pain, acute inflammatory pain, chronic inflammatory pain, andneuropathic pain), acute inflammation, chronic inflammation, rheumatoidarthritis, psoriasis, atopic dermatitis, asthma, bronchopulmonarydysplasia, COPD, adult respiratory disease, arthritis, inflammatorybowel disease, Crohn's disease, ulcerative colitis, septic shock,endotoxic shock, gram negative sepsis, toxic shock syndrome, stroke,ischemia reperfusion injury, renal reperfusion injury,glomerulonephritis, thrombosis, Alzheimer's disease, graft vs. hostreaction (i.e., graft-versus-host disease), allograft rejections (e.g.,acute allograft rejection, and chronic allograft rejection), malaria,acute respiratory distress syndrome, delayed type hypersensitivityreaction, atherosclerosis, cerebral ischemia, cardiac ischemia,osteoarthritis, multiple sclerosis, restinosis, angiogenesis, associatedwith tumor growth, osteoporosis, gingivitis, respiratory viruses, herpesviruses, hepatitis viruses, HIV, Kaposi's sarcoma associated virus(i.e., Kaposi's sarcoma), meningitis, cystic fibrosis, pre-term labor,cough, pruritis, multi-organ dysfunction, trauma, strains, sprains,contusions, psoriatic arthritis, herpes, encephalitis, CNS vasculitis,traumatic brain injury, systemic tumors, CNS tumors, tumors dependent onangiogenesis for growth, leukopenia and neutropenia,chemotherapy-induced leukopenia and neutropenia, opportunisticinfections associated with neutropenia or leukopenia, subarachnoidhemorrhage, post surgical trauma, interstitial pneumonitis,hypersensitivity, crystal induced arthritis, acute pancreatitis, chronicpancreatitis, acute alcoholic hepatitis, necrotizing enterocolitis,chronic sinusitis, angiogenic ocular disease, ocular inflammation,retinopathy of prematurity, diabetic retinopathy, macular degenerationwith the wet type preferred, corneal neovascularization, polymyositis,vasculitis, acne, gastric ulcers, duodenal ulcers, celiac disease,esophagitis, glossitis, airflow obstruction, airway hyperresponsiveness(i.e., airway hyperreactivity), bronchiectasis, bronchiolitis,bronchiolitis obliterans, chronic bronchitis, cor pulmonae, dyspnea,emphysema, hypercapnea, hyperinflation, hypoxemia, hyperoxia-inducedinflammations, hypoxia, surgical lung volume reduction, pulmonaryfibrosis, pulmonary hypertension, right ventricular hypertrophy,peritonitis associated with continuous ambulatory peritoneal dialysis(CAPD), granulocytic ehrlichiosis, sarcoidosis, small airway disease,ventilation-perfusion mismatching, wheeze, colds, gout, alcoholic liverdisease, lupus, burn therapy (i.e., the treatment of burns),periodontitis, cancer, transplant reperfusion injury, earlytransplantation rejection (e.g., acute allograft rejection) in a patientin need of such treatment comprising administering to said patient aneffective amount of the compound having the formula SX-682, or apharmaceutically acceptable salt or solvate thereof.

Another embodiment of this disclosure is a method for treating diseasessuch as allograft rejections, early transplantation rejections,autoimmune deafness, myocarditis, neuropathies, autoimmune diseases andvasculitis syndromes wherein said:

(a) allograft rejections are selected from the group consisting of acuteallograft rejections and chronic allograft rejections;

(b) early transplantation rejection is an acute allograft rejection;

(c) autoimmune deafness is Meniere's disease;

(d) myocarditis is viral myocarditis;

(e) neuropathies are selected from the group consisting of IgAneuropathy, membranous neuropathy and idiopathic neuropathy;

(f) autoimmune diseases are anemias; and

(g) vasculitis syndromes are selected from the group consisting of giantcell arteries, Behcet's disease and Wegener's granulomatosis.

Another embodiment of this disclosure is a method for treating COPD in apatient in need of such treatment comprising administering to saidpatient a therapeutically effective amount of the compound having theformula SX-682, or a pharmaceutically acceptable salt or solvatethereof.

Another embodiment of this disclosure is a method for treating arthritisin a patient in need of such treatment comprising administering to saidpatient a therapeutically effective amount of the compound having theformula SX-682, or a pharmaceutically acceptable salt or solvatethereof.

Another embodiment of this disclosure is a method for treatingosteoarthritis in a patient in need of such treatment comprisingadministering to said patient a therapeutically effective amount of thecompound having the formula SX-682, or a pharmaceutically acceptablesalt or solvate thereof.

Another embodiment of this disclosure is a method for treating pain in apatient in need of such treatment comprising administering to saidpatient a therapeutically effective amount of the compound having theformula SX-682, or a pharmaceutically acceptable salt or solvatethereof.

Another embodiment of this disclosure is a method for treating pain in apatient in need of such treatment comprising administering to saidpatient a therapeutically effective amount of the compound having theformula SX-682, or a pharmaceutically acceptable salt or solvatethereof, and administering a therapeutically effective amount of atleast one medicament selected from the group consisting of: NSAIDs,COXIB inhibitors (e.g., COX-1 and COX-2 inhibitors), anti-depressants,and anti-convulsants.

Another embodiment of this disclosure is a method for treating acutepain in a patient in need of such treatment comprising administering tosaid patient a therapeutically effective amount of the compound havingthe formula SX-682, or a pharmaceutically acceptable salt or solvatethereof.

Another embodiment of this disclosure is a method for treating acuteinflammatory pain in a patient in need of such treatment comprisingadministering to said patient a therapeutically effective amount of thecompound having the formula SX-682, or a pharmaceutically acceptablesalt or solvate thereof.

Another embodiment of this disclosure is a method for treating chronicinflammatory pain in a patient in need of such treatment comprisingadministering to said-patient a therapeutically effective amount of thecompound having the formula SX-682, or a pharmaceutically acceptablesalt or solvate thereof.

Another embodiment of this disclosure is a method for treatingneuropathic pain in a patient in need of such treatment comprisingadministering to said patient a therapeutically effective amount of thecompound having the formula SX-682, or a pharmaceutically acceptablesalt or solvate thereof.

Another embodiment of this disclosure is a pharmaceutical compositioncomprising the compound having the formula SX-682, or a pharmaceuticallyacceptable salt or solvate thereof, and at least one other agent,medicament, antibody and/or inhibitor disclosed above, and apharmaceutically acceptable carrier.

In general the compounds used to treat pain will have CXCR1/2antagonistic activity.

NSAIDs are well known to those skilled in the art and can be used intheir known dosages and dosage regimens. Examples of NSAIDs include butare not limited to: piroxicam, ketoprofen, naproxen, indomethacin, andibuprofen COXIB inhibitors are well known to those skilled in the artand can be used in their known dosages and dosage regimens. Examples ofCOXIB inhibitors include, but are not limited to: rofecoxib andcelecoxib. Anti-depressants are well known to those skilled in the artand can be used in their known dosages and dosage regimens. Examples ofanti-depressants include but are not limited to: amitriptyline andnortriptyline. Anti-convulsants are well known to those skilled in theart and can be used in their known dosages and dosage regimens. Examplesof anti-convulsants include but are not limited to: gabapentin,carbamazepine, pregabalin, and lamotragine.

Pharmaceutical Compositions

For preparing pharmaceutical compositions from the compound of formulaSX-682, inert, pharmaceutically acceptable carriers can be either solidor liquid. Solid form preparations include powders, tablets, dispersiblegranules, capsules, cachets and suppositories. The powders and tabletsmay be comprised of from about 5 to about 95 percent active ingredient.Suitable solid carriers are known in the art, e.g., magnesium carbonate,magnesium stearate, talc, microcrystalline cellulose, sugar or lactose.Tablets, powders, cachets and capsules can be used as solid dosage formssuitable for oral administration. Examples of pharmaceuticallyacceptable carriers and methods of manufacture for various compositionsmay be found in A. Gennaro (ed.), Remington: The Science and Practice ofPharmacy, 20th Edition, (2000), Lippincott Williams & Wilkins,Baltimore, Md. which is incorporated herein by reference.

Liquid form preparations include solutions, suspensions and emulsions.As an example may be mentioned water or water-propylene glycol solutionsfor parenteral injection or addition of sweeteners and opacifiers fororal solutions, suspensions and emulsions. Liquid form preparations mayalso include solutions for intranasal administration. Liquid formpreparations may also include dissolution in lipid-based,self-emulsifying drug delivery systems (SEDDS) such as Labrasol® orGelucire® for oral administration.

Aerosol preparations suitable for inhalation may include solutions andsolids in powder form, which may be in combination with apharmaceutically acceptable carrier, such as an inert compressed gas,e.g. nitrogen.

Also included are solid form preparations which are intended to beconverted, shortly before use, to liquid form preparations for eitheroral or parenteral administration. Such liquid forms include solutions,suspensions and emulsions.

The compound of formula SX-682 may also be deliverable transdermally.The transdermal composition can take the form of creams, lotions,aerosols and/or emulsions and can be included in a transdermal patch ofthe matrix or reservoir type as are conventional in the art for thispurpose.

The compound of formula SX-682 can be administered orally.

A suitable pharmaceutical preparation is in a unit dosage form. In suchform, the preparation is subdivided into suitably sized unit dosescontaining appropriate quantities of the active component, e.g., aneffective amount to achieve the desired purpose.

The quantity of active compound of formula SX-682 in a unit dose ofpreparation may be varied or adjusted from about 0.01 mg to about 1000mg, or from about 0.01 mg to about 750 mg, or from about 0.01 mg toabout 500 mg, or from about 0.01 mg to about 250 mg, according to theparticular application.

The actual dosage employed may be varied depending upon the requirementsof the patient and the severity of the condition being treated.Determination of the proper dosage regimen for a particular situation iswithin the skill of the art. For convenience, the total dosage may bedivided and administered in portions during the day as required.

The amount and frequency of administration of the compound of formulaSX-682 and/or the pharmaceutically acceptable salts thereof will beregulated according to the judgment of the attending clinicianconsidering such factors as age, condition and size of the patient aswell as severity of the symptoms being treated. A typical recommendeddaily dosage regimen for oral administration can range from about 0.04mg/day to about 4000 mg/day, in two to four divided doses, or givenpreferably as a single once-daily dose. Once-weekly and twice-weeklydosing is also preferable.

The amount and frequency of administration of the compound of formulaSX-682 and the chemotherapeutic agents and/or radiation therapy will beregulated according to the judgment of the attending clinician(physician) considering such factors as age, condition and size of thepatient as well as severity of the disease being treated. A dosageregimen of the compound having the formula SX-682 can be orallyadministration of from 10 mg to 2000 mg/day, or 10 to 1000 mg/day, or 50to 600 mg/day, in two to four (or two) divided doses, to block tumorgrowth. Intermittent therapy (e.g., one week out of three weeks or threeout of four weeks) may also be used.

The chemotherapeutic agent and/or radiation therapy can be administeredaccording to therapeutic protocols well known in the art. It will beapparent to those skilled in the art that the administration of thechemotherapeutic agent and/or radiation therapy can be varied dependingon the disease being treated and the known effects of thechemotherapeutic agent and/or radiation therapy on that disease. Also,in accordance with the knowledge of the skilled clinician, thetherapeutic protocols (e.g., dosage amounts and times of administration)can be varied in view of the observed effects of the administeredtherapeutic agents (i.e., antineoplastic agent or radiation) on thepatient, and in view of the observed responses of the disease to theadministered therapeutic agents.

If the compound of formula SX-682, and the chemotherapeutic agent and/orradiation is not administered simultaneously or essentiallysimultaneously, then the initial order of administration of the compoundof formula SX-682, and the chemotherapeutic agent and/or radiation, maynot be important. Thus, the compound of formula SX-682 may beadministered first, followed by the administration of thechemotherapeutic agent and/or radiation; or the chemotherapeutic agentand/or radiation may be administered first, followed by theadministration of the compound of formula SX-682. This alternateadministration may be repeated during a single treatment protocol. Thedetermination of the order of administration, and the number ofrepetitions of administration of each therapeutic agent during atreatment protocol, is well within the knowledge of the skilledphysician after evaluation of the disease being treated and thecondition of the patient.

For example, the chemotherapeutic agent and/or radiation may beadministered first, especially if it is a cytotoxic agent, and then thetreatment continued with the administration of the compound having theformula SX-682 followed, where determined advantageous, by theadministration of the chemotherapeutic agent and/or radiation, and so onuntil the treatment protocol is complete.

The particular choice of the compound of formula SX-682, andchemotherapeutic agent and/or radiation will depend upon the diagnosisof the attending physicians and their judgment of the condition of thepatient and the appropriate treatment protocol.

Also, in general, the compound of formula SX-682 and thechemotherapeutic agent do not have to be administered in the samepharmaceutical composition, and may, because of different physical andchemical characteristics, have to be administered by different routes.For example, the compound of formula SX-682 may be administered orallyto generate and maintain good blood levels thereof, while thechemotherapeutic agent may be administered intravenously. Thedetermination of the mode of administration and the advisability ofadministration, where possible, in the same pharmaceutical composition,is well within the knowledge of the skilled clinician. The initialadministration can be made according to established protocols known inthe art, and then, based upon the observed effects, the dosage, modes ofadministration and times of administration can be modified by theskilled clinician.

Thus, in accordance with experience and knowledge, the practicingphysician can modify each protocol for the administration of a component(therapeutic agent; i.e., the compound of formula SX-682,chemotherapeutic agent or radiation) of the treatment according to theindividual patient's needs, as the treatment proceeds.

The attending clinician, in judging whether treatment is effective atthe dosage administered, will consider the general well-being of thepatient as well as more definite signs such as relief of disease-relatedsymptoms, inhibition of tumor growth, actual shrinkage of the tumor, orinhibition of metastasis. Size of the tumor can be measured by standardmethods such as radiological studies, e.g., CAT or MRI scan, andsuccessive measurements can be used to judge whether or not growth ofthe tumor has been retarded or even reversed. Relief of disease-relatedsymptoms such as pain, and improvement in overall condition can also beused to help judge effectiveness of treatment.

The disclosure provided herein is exemplified by the followingpreparations and examples that should not be construed to limit thescope of the disclosure. Alternative mechanistic pathways and analogousstructures may be apparent to those skilled in the art.

Synthesis Example 1 Synthesis ofN-(4-fluorophenyl)-2-chloro-pyrimidinamide 3

2-Chloro-pyrimidine-5-carboxylic acid 1 (3.16 g, 20 mmol) was suspendedin dichloromethane (40 mL), and oxalyl chloride (3.30 g, 26 mmol) wasadded, followed by dimethylformamide (3 drops) as catalyst. The reactionstarted to vigorously evolve gas. The reaction was heated to reflux for1 hour, then allowed to cool to room temperature. 4-fluoroaniline wasadded, vigorous bubbling was seen again, and the reaction mixture warmedup considerably. Triethylamine was added, and a flocculent precipitateimmediately formed. The reaction mixture was heated to reflux once againfor another hour, removed from heat, and stirred at room temperature for18 hours under nitrogen. The reaction was diluted with ethyl acetate(100 mL), and the organic layer washed with water, saturated sodiumbicarbonate, water, 1N HCl, water, saturated sodium chloride, then driedover sodium sulfate. The liquid was filtered, and evaporated to yield3.44 g (68%) of compound 3 as a light yellow solid. ESI-MS m/z=252.0[M+H]⁺.

Synthesis Example 2 Synthesis of Mercapto-pyrimidine-6-carboxylic acid(4-fluoro-phenyl)-amide Intermediate 4

In a round bottom flask, 2-Chloro-pyrimidine-5-carboxylic acid(4-fluoro-phenyl)-amide 3 (2.52 g, 10.0 mmol) and anhydrous sodiumhydrogen sulfide (1.22 g, 21.8 mmol) were suspended in anhydrousdimethylformamide (20 mL). The suspension was stirred at roomtemperature, and the reaction mixture turned a deep green color. After 1h, the reaction mixture was partioned between ethyl acetate and water,and transferred to a separatory funnel After the layers were separated,the ethyl acetate layer was washed twice with a 2:1 mixture of water and5% sodium bicarbonate. The combined aqueous layers were acidified with 1N HCl precipitating a yellow solid. The suspension was left to stand atroom temperature for 2 hours, then the precipitate was collected byvacuum filtration, rinsing with water. The yellow solid was driedovernight in a vacuum desiccator to yield 2.3 g (92%) of thethiopyrimidinamide intermediate 4. ESI-MS m/z=250.0 [M+H]⁺. ¹H NMR (300MHz, DMSO-d₆) δ 10.29 (s, 1H), 8.77 (bs, 2H), 7.77-7.70 (m, 2H), 7.24(t, J=8.9 Hz, 2H).

Synthesis Example 3 Synthesis of Pinacol Ester Derivative 5

2-Mercapto-pyrimidine-5-carboxylic acid (4-fluoro-phenyl)-amideintermediate 4 (2.32 g, 9.3 mmol) and2-bromomethyl-4-trifluoromethoxy-phenylboronic acid, pinacol ester (3.85g, 10.1 mmol) were suspended in anhydrous DMF (20 ml). Sonication wasused to dissolve the compounds. To the reaction flask triethylamine (2.8mL, 20.1 mmol) was added and a precipitate (triethylamine-HBr) formedimmediately. The reaction was layered with nitrogen gas and left tostand at room temperature for 3.75 hr. The reaction was poured intowater (500 mL) and layered with ethyl acetate. The biphasic solution wastransferred to a separatory funnel and diluted further with ethylacetate and brine. The layers were separated, and the aqueous layer wasextracted twice more with ethyl acetate. The combined ethyl acetatelayers were dried over sodium sulfate, gravity filtered, and dried invacu to yield 5.7 g (>100%, 93% pure by LC-MS) of a red oil,2-[2-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-5-trifluoromethoxy-benzylsulfanyl]-pyrimidine-5-carboxylicacid (4-fluoro-phenyl)-amide 6. ESI-MS m/z=550.1 [M+H]⁺. ¹H NMR (500MHz, DMSO-d₆) δ 10.52 (s, 1H), 9.11 (s, 2H), 7.81 (d, J=8.2 Hz, 1H),7.78-7.75 (m, 2H), 7.55 (s, 1H), 7.28-7.22 (m, 3H), 4.72 (s, 2H), 1.32(s, 12H). The NMR spectrum also contained peaks consistent with thepresence of residual DMF. The product was carried forward withoutfurther purification.

Synthesis Example 4 Synthesis of Compound SX-682

SX-682 was obtained by deprotection of the boronic acid pinacol esterusing a method modified from Yuen et al, Tetrahedron Letters46:7899-7903. Compound 6 (5.66 g, 10.3 mmol, 1 eq.) was dissolved inmethanol (100 mL). The reaction vessel was charged with 4.5 M aqueouspotassium hydrogen fluoride (11.5 mL, 5 eq.) and the resulting orangesolution was stirred for 1 hour. The methanol was removed by rotaryevaporation at room temperature and the resulting mixture of yellow andoff-white solids was suspended in acetone. The suspension was gravityfiltered to remove the insoluble salts, and the resulting clear yellowsolution was added via pipette to a flask of water (2 L) and placed inthe refrigerator. After cooling for about 1.5 hours, the resultingoff-white precipitate was collected by vacuum filtration, rinsing withwater. The funnel was dried overnight in a vacuum desiccator to afford3.87 g (80% yield, >99% purity by LC-MS) of 2-(2-Boronicacid-5-trifluoromethoxy-benzylsulfanyl)-pyrimidine-5-carboxylic acid(4-fluoro-phenyl)-amide. ESI-MS m/z=468.1 [M+H]⁺. ¹H NMR (300 MHz,DMSO-d6) δ 10.49 (s, 1H), 9.09 (s, 2H), 8.33 (bs, 2H), 7.78-7.73 (m,2H), 7.66 (d, J=8.5 Hz, 1H), 7.46 (s, 1H), 7.25-7.19 (m, 3H), 4.70 (s,2H).

Pharmacology Example 1 In Vitro Inhibition of Intracellular CalciumRelease by SX-682

An in vitro assay showed inhibition of CXCR1/2-mediated intracellularcalcium release by SX-682. Briefly, cells (either isolated humanneutrophils or RBL cells stably transfected with either CXCR1 or CXCR2)were suspended in HBSS⁻ (without Ca²⁺ and Mg²⁺) containing 10 mM HEPESand FLIPR Calcium 3 dye (3.1×10⁷ cells in total volume 1.7 mL). Cellswere aliquoted (200 μL of the cell suspension per tube, 8 tubes total)and 2 μL of the designated compound (with appropriate dilutions) wereadded to each of 6 tubes. As controls, 2 μL of DMSO (1% finalconcentration) were added to 2 other tubes. Cells were incubated for 30min at 37° C. After dye loading, tubes were centrifuged at 6,000 rpm for1 min, supernatant was removed and the cell pellet was re-suspended in200 μL of HBSS⁺ (with Ca²⁺ and Mg²⁺) containing 10 mM HEPES. The testcompound or DMSO (control) was added again at the same concentrationsthat were used during cell loading. The cell suspension was aliquotedinto a 96-well Reading Plate (Corning) in a volume of 90 μL (10⁵cells/well). The Compound Plate contained agonist (CXCL8 in HBSS⁻) orHBSS⁻ (control). After 15 sec of reading the basal level of fluorescenceby FlexStation II, 10 μL of CXCL8 or HBSS⁻ were automaticallytransferred from the Compound Plate into the Reading Plate (finalconcentration of CXCL8 was 25 nM). Changes in fluorescence weremonitored (λ_(ex)=485 nm, λ_(em)=525 nm) every 5 s for 240 to 500 s atroom temperature.

The maximum change in fluorescence, expressed in arbitrary units overbaseline (Max-Min), was used to determine the CXCL8 response. The effectof each compound on the CXCL8 response was normalized and expressed as apercent of the DMSO control, which was designated as “100% response.”Curve fitting and calculation of the compound inhibitory concentrationthat reduces the level of the CXCL8 response by 50% (IC₅₀), or thecompound agonist concentration that increases the level of the calciumrelease by 50% of the maximum agonist-induced change (EC₅₀) weredetermined by nonlinear regression analysis of the dose-response curvesgenerated using Prism 4 (GraphPad Software, Inc., San Diego, Calif.).

The mean (±SE) IC₅₀ for SX-682 (n=4) was 42±3 nM, 20±2 nM and 55±6 nM inCXCR1 transfected RBL cells (‘CXCR1’, squares), CXCR2 transfected RBLcells (‘CXCR2’, inverted triangles), and human neutrophils (‘HumanPMNs’, circles), respectively (see FIG. 1).

Pharmacology Example 2 SX-682 Exhibits Sustained Wash-ResistantInhibition of Intracellular Calcium Release

SX-682 contains a boronic acid moiety that has the potential to form atransient covalent linkage with hydroxyl-bearing amino acid side chainsin the binding site of its protein target. Without wishing to be boundby theory, we hypothesized that such a transient covalent linkage in thebinding site of SX-682 might result in CXCR1/2 inhibition that wassustained after inhibitor washout. If inhibition is sustained in vitroafter SX-682 washout, inhibition may also be sustained in vivo afterSX-682 has been eliminated from the plasma, a property that would permitinfrequent patient dosing regimens (e.g. once-daily, twice-weekly andonce-weekly). Infrequent dosing regimens are preferred embodiments.

In order to test this hypothesis, RBL cells (10⁷ cells/mL) stablytransfected with either CXCR1 or CXCR2 were (1) incubated with SX-682 atvarious concentrations for 30 minutes at 37° C., (2) washed andresuspended in assay buffer (RPMI/2% serum) at room temperature, and (3)assayed for CXCL8-mediated calcium response at time points up to 12 hafter inhibitor washout. The concentrations of SX-682 tested were 0(positive control), 0 (negative control), 0.4, 2, and 10 μM. At 30minutes before each time point, a 56.25 μL aliquot of the cells wereremoved and loaded for 30 minutes at room temperature in the dark withFLIPR-3 reagent (262.5 μL per tube). Following FLIPR-3 incubation, cellswere assayed for CXCL8 mediated intracellular calcium release asdescribed in Pharmacology Example 1.

Consistent with our hypothesis, SX-628 exhibited inhibition ofCXCL8-mediated intracellular calcium flux in RBL cells stablytransfected with either CXCR1 (see FIG. 2) or CXCR2 (see FIG. 3) thatwas sustained for at least 12 hours after SX-682 washout.

Pharmacology Example 3 SX-682 Exhibits Pronounced Activity in the RatModel of Pulmonary Inflammation

SX-682 was assayed in an in vivo rat model of pulmonary inflammation.Activity in this model of pulmonary inflammation provides evidence thatsupports the use of SX-682 in the treatment of a number of pulmonaryinflammatory diseases, including chronic obstructive pulmonary disease(COPD) and bronchopulmonary dysplasia (BPD). In this experiment,Sprague-Dawley rats (n=4 per cohort) were dosed intravenously only onceat t=0 with either vehicle control (dimethylformamide/PEG400/saline,40:40:20), positive inhibitor control (SX-576, 1 mg/kg) or the testcompound (SX-682, 1 mg/kg). The rats were then placed in air (negativeexposure group; vehicle control only) or 1 ppm ozone (positive exposuregroup; vehicle control, positive inhibitor control SX-576, and testcompound SX-682) for 4 hours. The rats were then sacrificed at t=24hours, and the bronchoalveolar lavage fluid (BALF) was collected. Thecells were spun down, stained with Wright-Giemsa and counted. In thenegative exposure group, no neutrophils were observed when stained. Inthe ozone exposed rats treated with vehicle however, there was a briskinflux of neutrophils of approximately 14,000 per mL of BALF (see FIG.4). In contrast, both SX-576 and SX-682 (each at 1 mg/kg) significantlydecreased the influx of neutrophils into the lungs as compared tocontrol rats treated with vehicle only (FIG. 4). Of the two inhibitorstested, SX-682 exhibited a markedly more robust inhibition of neutrophilchemotaxis (FIG. 4). Notably, the inhibition of neutrophil influx intothe BALF was sustained for 24 hours after only a single dose of 1 mg/kgof SX-682. These results provide evidence that SX-682 is a potentinhibitor of pulmonary neutrophil chemotaxis in vivo, and is effectivefor treating diseases with a heightened pulmonary inflammationcomponent, like COPD in a predictive in vivo model.

Metabolic Stability Example 1 Increased Microsomal Stability of SX-682

Liver microsomes are an in vitro model for in vivo metabolism andelimination of a drug by the liver (and gut) cytochrome P450 system. Acompound's stability in liver microsomes in vitro is predictive of itsmetabolism and elimination in vivo. We examined the stability of SX-682in liver microsomes together with several other cogeners to quantify themicrosomal stability of SX-682 and identify potential structure-activityrelationships (SAR) predictive of stability or instability (see FIG. 5).

The compounds were incubated in duplicate with human liver microsomes at37° C. The reaction contained microsomal protein in 100 mM potassiumphosphate, 2 mM NADPH, 3 mM MgCl₂, pH 7.4. A control was run for eachcompound omitting NADPH to detect NADPH-independent degradation. Analiquot was removed from each experimental and control reaction at 0,10, 20, 30, and 60 minutes and mixed with an equal volume of ice-coldStop Solution (0.3% acetic acid in acetonitrile containing haloperidol,diclofenac, or other internal standard). Stopped reactions wereincubated for at least ten minutes at −20° C., and an additional volumeof water was added. The samples were centrifuged to remove precipitatedprotein, and the supernatants were analyzed by LCMS/MS to quantitate theremaining compound. Data were converted to percent remaining by dividingby the time zero concentration value. Data were fit to a first-orderdecay model to determine half-life. Intrinsic clearance was calculatedfrom the half-life and the protein concentrations:CL_(int)=ln(2)/(t½[microsomal protein]).

The results are shown in Table 1. Surprisingly, SX-682 was markedly morestable than SX-671 or SX-576 (6-fold larger half life), even though thelatter is structurally identical but for a single ring nitrogen. On theother hand, the introduction of a ring nitrogen was insufficient aloneto impart the stability seen with SX-682 as demonstrated by SX-677 andSX-678, which have half lives that are 2-fold and 5-fold smaller thanSX-682, respectively. More surprising is that eliminating the ringnitrogen in SX-517 yielded a half-life even larger than that of SX-682.The results as a whole led to no SAR predictive of the surprisingstability of SX-682.

TABLE 1 Stability in human liver microsomes (NADPH-dependent) ParameterSX-517 SX-576 SX-671 SX-677 SX-678 SX-682 CL_(int) ^(a) (μL/min mg) 3.445.7 16.2 15.9 33.4 2.1 t½^(b) (min) 405 50 143 145 69.2 325^(a)Microsomal intrinsic clearance. ^(b)Half-life.

Metabolic Stability Example 2 Increased Plasma Stability of SX-682

The in vitro stability of SX-682 and the cogeners of Metabolic StabilityExample 1 (FIG. 5) were further studied in human plasma. The reactionswere initiated by the addition of 5 μL of a 500 μM DMSO stock solutionto 495 μL of preheated plasma solution to yield a final concentration of5 μM. The assays were performed in a heat block at 37° C. and conductedin duplicate. Samples (50 μL) were taken at 0, 30, 60, 120, 240 min andadded to 150 μL acetonitrile in order to deproteinize the plasma. Thesamples were subjected to vortex mixing for 1 min and thencentrifugation for 15 min at 14,000 rpm. The clear supernatants wereanalyzed by LC-MS.

The in vitro plasma half life (t½) was calculated using the expressiont½=ln(2)/b, where b is the slope found in the linear fit of the naturallogarithm of the fraction remaining of the parent compound vs.incubation time.

The results are shown in Table 2. In the case of plasma stability,SX-682 is roughly as stable as SX-576 in contradistinction to itsmarkedly enhanced stability in liver microsomes. Apparently, eliminatingthe ring nitrogen has little impact on plasma stability. On the otherhand, also changing the sulfur to oxygen in SX-671 resulted in apronounced 35-fold reduction in plasma half-life. However, keeping thesulfur is insufficient alone to maintain plasma stability as illustratedby SX-517, which maintains the sulfur but eliminates the ring F₃CO groupand results in a 5-fold reduction in plasma half-life.

TABLE 2 Stability in human plasma (incubation at 37° C., LC-MS/MSdetection) Parameter SX-517 SX-576 SX-671 SX-677 SX-678 SX-682 t½^(b)(min) 113 533 21 2310 3465 693

What is claimed is:
 1. A compound having formula SX-682

or a pharmaceutically acceptable salt or solvate thereof.
 2. Apharmaceutical formulation comprising the compound of claim 1 or apharmaceutically acceptable salt or solvate thereof.
 3. Thepharmaceutical formulation of claim 2, wherein the compound of claim 1is in a powder, solution, suspension, emulsion, or surface deposited ona suitable pharmaceutical excipient for inhalation or oraladministration.
 4. A method for treating rheumatoid arthritis, strokeand ischemia reperfusion injury, psoriasis, chronic obstructivepulmonary disease, or bronchopulmonary dysplasia in a patient in need ofsuch treatment, comprising administering an effective amount of thecompound having formula SX-682:

or a pharmaceutically acceptable salt or solvate thereof.
 5. The methodof claim 4, wherein the compound having formula SX-682 is administeredorally, transdermally, parenterally, intranasally, or by inhalation. 6.The method of claim 4, wherein the compound having formula SX-682 isco-administered with a chemotherapeutic agent.
 7. The method of claim 4,wherein the compound having formula SX-682 is administered in a 0.01 mgto 1000 mg dose.
 8. The method of claim 4, wherein the compound havingformula SX-682 is administered in a 0.01 mg to 7500 mg dose.
 9. Themethod of claim 4, wherein the compound having formula SX-682 isadministered in a 0.01 mg to 500 mg dose.
 10. The method of claim 4,wherein the compound having formula SX-682 is administered orally or byinhalation in a daily, twice-weekly or once-weekly dose of 0.04 mg to4000 mg, given in two to four divided doses or as a single dose.
 11. Themethod of claim 10, wherein the dose of the compound having formulaSX-682 is 10 mg to 2000 mg.
 12. The method of claim 10, wherein the doseof the compound having formula SX-682 is 10 mg to 1000 mg.
 13. Themethod of claim 10, wherein the dose of the compound having formulaSX-682 is 50 mg to 600 mg.
 14. A method of making a compound having theformula SX-682

comprising reacting 2-chloro-pyrimidine-5-carboxylic acid with4-fluoroaniline to produce N-(4-fluorophenyl)-2-chloro-pyrimidinamide.15. The method of claim 14, further comprising reactingN-(4-fluorophenyl)-2-chloro-pyrimidinamide with sodium hydrogen sulfideto produce 2-mercapto-pyrimidine-5-carboxylic acid(4-fluoro-phenyl)-amide.
 16. The method of claim 15, further comprisingreacting 2-mercapto-pyrimidine-5-carboxylic acid (4-fluoro-phenyl)-amidewith 2-bromomethyl-4-trifluoromethoxy-phenylboronic acid, pinacol esterto produce a pinacol ester derivative having the formula I


17. The method of claim 15, further comprising deprotection of theboronic acid pinacol ester of formula I by reaction with potassiumhydrogen fluoride.